Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Nina Höller

Nariae Baik-Schneditz

Bernhard Schwaberger

Lukas Peter Mileder

Niels Hammer

Gerhard Pichler

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Kargl, J; Balenga, NA; Platzer, W; Martini, L; Whistler, JL; Waldhoer, M.
The GPCR-associated sorting protein 1 regulates ligand-induced down-regulation of GPR55.
Br J Pharmacol. 2012; 165(8):2611-2619 Doi: 10.1111/j.1476-5381.2011.01562.x [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz: Kargl Julia; Waldhoer Maria
Co-Autor*innen der Med Uni Graz: Aghaei Bandbon Balenga Nariman; Platzer Wolfgang
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Abstract:: BACKGROUND AND PURPOSE Many GPCRs, including the CB1 cannabinoid receptor, are down-regulated following prolonged agonist exposure by interacting with the GPCR-associated sorting protein-1 (GASP-1). The CB1 receptor antagonist rimonabant has also recently been described to be an agonist at GPR55, a cannabinoid-related receptor. Here we investigated the post-endocytic properties of GPR55 after agonist exposure and tested whether GASP-1 is involved in this process. EXPERIMENTAL APPROACH We evaluated the direct protein-protein interaction of GPR55 with GASP-1 using (i) GST-binding assays and (ii) co-immunoprecipitation assays in GPR55-HEK293 cells with endogenous GASP-1 expression. We further tested the internalization, recycling and degradation of GPR55 using confocal fluorescence microscopy and biotinylation assays in the presence and absence of GASP-1 (lentiviral small hairpin RNA knockdown of GASP-1) under prolonged agonist [rimonabant (RIM), lysophosphatidylinositol (LPI)] stimulation. KEY RESULTS We showed that the prolonged activation of GPR55 with rimonabant or LPI down-regulates GPR55 via GASP-1. GASP-1 binds to GPR55 in vitro, and this interaction was required for targeting GPR55 for degradation. Disrupting the GPR55-GASP-1 interaction prevented post-endocytic receptor degradation, and thereby allowed receptor recycling. CONCLUSION AND IMPLICATIONS These data implicate GASP-1 as an important regulator of ligand-mediated down-regulation of GPR55. By identifying GASP-1 as a key regulator of the trafficking and, by extension, functional expression of GPR55, we may be one step closer to gaining a better understanding of this receptor in response to cannabinoid drugs.
Find related publications in this database (using NLM MeSH Indexing): Down-Regulation -; Glutathione Transferase - metabolism; HEK293 Cells -; Humans -; Ligands -; Lysophospholipids - pharmacology; Piperidines - pharmacology; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB1 - antagonists and inhibitors; Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - metabolism; Recombinant Fusion Proteins - metabolism; Vesicular Transport Proteins - metabolism
Find related publications in this database (Keywords): GPCR; GASP-1; degradation; GPR55; LPI; rimonabant